Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines
A series of 12 polysubstituted pyrrolo[3,4-<i>b</i>]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi−3CR/<i>aza</i> Diels-Alder/<i>N</i>-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcino...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-07-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/24/14/2648 |
| _version_ | 1818172506048036864 |
|---|---|
| author | Daniel Segura-Olvera Ailyn N. García-González Ivette Morales-Salazar Alejandro Islas-Jácome Yareli Rojas-Aguirre Ilich A. Ibarra Erik Díaz-Cervantes Sofía Lizeth Alcaraz-Estrada Eduardo González-Zamora |
| author_facet | Daniel Segura-Olvera Ailyn N. García-González Ivette Morales-Salazar Alejandro Islas-Jácome Yareli Rojas-Aguirre Ilich A. Ibarra Erik Díaz-Cervantes Sofía Lizeth Alcaraz-Estrada Eduardo González-Zamora |
| author_sort | Daniel Segura-Olvera |
| collection | DOAJ |
| description | A series of 12 polysubstituted pyrrolo[3,4-<i>b</i>]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi−3CR/<i>aza</i> Diels-Alder/<i>N</i>-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αβ-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αβ-tubulin. In consequence, it was determined that hydrophobic−aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand−target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αβ-tubulin. |
| first_indexed | 2024-12-11T19:13:41Z |
| format | Article |
| id | doaj.art-6ec9864ca153498a84ce9eef4f982be4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T19:13:41Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6ec9864ca153498a84ce9eef4f982be42022-12-22T00:53:43ZengMDPI AGMolecules1420-30492019-07-012414264810.3390/molecules24142648molecules24142648Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell LinesDaniel Segura-Olvera0Ailyn N. García-González1Ivette Morales-Salazar2Alejandro Islas-Jácome3Yareli Rojas-Aguirre4Ilich A. Ibarra5Erik Díaz-Cervantes6Sofía Lizeth Alcaraz-Estrada7Eduardo González-Zamora8Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, MexicoDepartamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, MexicoDepartamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, MexicoDepartamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, MexicoDepartamento de Polímeros, Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Coyoacán, Mexico City C.P. 04510, MexicoLaboratorio de Fisicoquímica y Reactividad de Superficies, Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Coyoacán, Mexico City C.P. 04510, MexicoDepartamento de Alimentos, Centro Interdisciplinario del Noreste, Universidad de Guanajuato, Tierra Blanca, Guanajuato C.P. 37975, MexicoDivisión de Medicina Genómica, Centro Médico Nacional 20 de Noviembre, ISSSTE, Félix Cuevas 540, Col. Del Valle Sur, Benito Juárez, Mexico City C.P. 03100, MexicoDepartamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, MexicoA series of 12 polysubstituted pyrrolo[3,4-<i>b</i>]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi−3CR/<i>aza</i> Diels-Alder/<i>N</i>-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αβ-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αβ-tubulin. In consequence, it was determined that hydrophobic−aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand−target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αβ-tubulin.https://www.mdpi.com/1420-3049/24/14/2648pyrrolo[3,4-<i>b</i>]pyridin-5-onespaclitaxelαβ-tubulincervical cancerSiHaHeLaCaskimolecular dockingQSARpharmacophore model |
| spellingShingle | Daniel Segura-Olvera Ailyn N. García-González Ivette Morales-Salazar Alejandro Islas-Jácome Yareli Rojas-Aguirre Ilich A. Ibarra Erik Díaz-Cervantes Sofía Lizeth Alcaraz-Estrada Eduardo González-Zamora Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines Molecules pyrrolo[3,4-<i>b</i>]pyridin-5-ones paclitaxel αβ-tubulin cervical cancer SiHa HeLa Caski molecular docking QSAR pharmacophore model |
| title | Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines |
| title_full | Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines |
| title_fullStr | Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines |
| title_full_unstemmed | Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines |
| title_short | Synthesis of Pyrrolo[3,4-<i>b</i>]pyridin-5-ones via Multicomponent Reactions and In Vitro–In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines |
| title_sort | synthesis of pyrrolo 3 4 i b i pyridin 5 ones via multicomponent reactions and in vitro in silico studies against siha hela and caski human cervical carcinoma cell lines |
| topic | pyrrolo[3,4-<i>b</i>]pyridin-5-ones paclitaxel αβ-tubulin cervical cancer SiHa HeLa Caski molecular docking QSAR pharmacophore model |
| url | https://www.mdpi.com/1420-3049/24/14/2648 |
| work_keys_str_mv | AT danielseguraolvera synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT ailynngarciagonzalez synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT ivettemoralessalazar synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT alejandroislasjacome synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT yarelirojasaguirre synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT ilichaibarra synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT erikdiazcervantes synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT sofializethalcarazestrada synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines AT eduardogonzalezzamora synthesisofpyrrolo34ibipyridin5onesviamulticomponentreactionsandinvitroinsilicostudiesagainstsihahelaandcaskihumancervicalcarcinomacelllines |